Abstract 307: Endothelial mPGES-1 Mediates Thiazolidinedione-Induced Adipose-Specific Capillary Hyperpermeability and Fluid Retention
Thiazolidinedione-induced fluid retention results from two prominent mechanisms: increased distal tubular fluid reabsorption and adipose-specific increases in capillary permeability; the later mechanism requires activation of endothelial but not smooth muscle PPARγ as demonstrated by using conditional knockout mice (Yang et al. 63rd High Blood Pressure Research Conference. #063, 2009). The present study examined the role of microsomal prostaglandin E synthase-1 (mPGES-1) in TZD-induced capillary hyperperbeability in the adipose tissues. Following rosiglitazone (RGZ) treatment, remarkable COX-2 and mPGES-1 inductions were detected at day 1 and peaked at day 2 (COX-2:104-fold for mRNA and 98-fold for protein; mPGES-1: 2.5-fold for mRNA and 30-fold for protein) in parallel with a 64-fold increase in PGE2 production in apidydimal fat depot (AFD) but not in other tissues tested, and declined at day 14. Body weight gain (BWG) in response to RGZ in WT mice were 1.62 g on day 14. In contrast, the BWG in mPGES-1 KO mice was completely blocked on day 7 and was reduced by 60% on day 14. RGZ-treated WT mice exhibited a 60% increase in water content in the AFD, which was significantly attenuated in the KO mice. In parallel, the capillary perbeability in the adipose tissue, as assessed by Evans blue leakage assay, exhibited a 60% increase in WT mice after RGZ treatment. As compared with WT controls, the adipose capillary permeability in the KO mice was 60% less at baseline and 100% less after RGZ treatment. RGZ-induced fluid retention was further tested in mice lacking mPGES-1 in endothelium or smooth muscle generated respectively by crossing mPGES-1 floxed mice with Tie-2-Cre or SM22-Cre mice (termed EC KO or SM KO). In EC KO mice, TZD-induced capillary hyperpermeability in adipose tissue was completely abolished, associated with a 50% reduction of the BWG and complete blockade of PGE2 stimulation in the ADF, a phenotype analogous to that of endothelial PPARγ KO mice. In contrast, neither water content nor capillary permeability in the skeletal muscle was affected by RGZ treatment. Taken together, this study has defined endothelial mPGES-1 as a key mediator of TZD-induced adipose-specific capillary hyperperbeability and fluid retention.
- © 2012 by American Heart Association, Inc.